Pediculicidal composition

ABSTRACT

The disclosure provides a pediculicidal composition comprising a metal chelating agent; a carrier vehicle comprising water and an activating solvent system comprising an alcohol and a hydrocarbon. The carrier vehicle may be in the form of a solution, a cream, an ointment, a foam, a spray, an emulsion or a gel. The disclosure also provides method for use of a pediculicidal composition to treat human head lice and their eggs and methods for controlling head lice infestation.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to U.S.Provisional Patent Application Ser. No. 61/917,078, filed Dec. 17, 2013,which is incorporated herein by reference in its entirety.

FIELD

The present invention relates to compositions and methods for treatinghuman head lice, Pediculus humanus capitis. In particular, the inventionrelates to a pediculicidal composition and the methods of use.

BACKGROUND

Head lice persist in developed and underdeveloped countries despite theavailability of modern chemical insecticide treatments, public healtheducation, and community based programs of lice eradication. Thepersistence of head lice is due to a combination of factors. Some licecontrol programs suffer logistical problems. Additionally, while shampooformulations continue to retain widespread popularity, some chemicaltreatments are not entirely effective.

Various compositions and methods have been used to treat a head liceinfestation. For example, lice and their eggs are mechanically removedwith combs and killed with insecticides (known as pediculicides).Pediculicides, or pediculicidal compositions, are used to treat liceinfestations and hence typically display both lousicidal and ovicidalactivity. For example, lindane and various pyrethroids, have been usedin conjunction with shampoos for treating head lice infestations.However, the use of these compositions and methods is not entirelyeffective in controlling head lice because some lice or their eggs(nits) often survive the treatment. Lice have also begun to developresistance to current pediculicides and thus a new compound for killinglice and their eggs is desirable.

Accordingly, there remains a need for pediculicidal compositions thatare easy to use and are highly effective against lice and their eggs.The present invention addresses these unmet needs.

SUMMARY

The disclosure relates to compositions and methods for treating humanhead lice, Pediculus humanus capitis. In particular, the disclosure isdirected to pediculicidal compositions and methods of use, as well as touses of the compositions for treating infestation on a host. In anembodiment, the pediculicidal composition comprises: a metal chelatingagent, an oil phase comprising an activating solvent system, and anaqueous phase which combines with the oil phase to form a carriervehicle. More specific embodiments relate to compositions comprising5,5′-dimethyl-2,2′-dipyridyl; an oil phase comprising an activatingsolvent system that comprising an alcohol and a hydrocarbon; and anaqueous phase which combines with the oil phase to form a carriervehicle.

In an aspect, the disclosure provides a composition comprising5,5′-dimethyl-2,2′-dipyridyl; a carrier vehicle comprising an activatingsolvent system comprising an alcohol and a hydrocarbon; and an aqueousphase which combines to form the carrier vehicle; wherein5,5′-dimethyl-2,2′-dipyridyl is present in the composition at aconcentration from about 0.25% by weight or greater wherein saidcomposition exhibits both ovicidal and lousicidal activity. In someembodiments the alcohol comprises an aromatic or aryl alcohol such as,for example benzyl alcohol or phenoxyethanol. In some embodiments thehydrocarbon comprises mineral oil. In further embodiments, thecomposition may comprise 5,5′-dimethyl-2,2′-dipyridyl at a concentrationfrom about 0.25% to about 5% by weight, or from about 0.5% to about 5%by weight, or from about 0.25% to about 1%, or from about 0.5% to about1% by weight. In some embodiments the carrier vehicle in the compositioncan be formulated as a solution, a gel, a cream, an ointment, a foam, aspray or an emulsion. In some embodiments, the carrier vehicle maycomprise water, the activating solvent system, and at least one agentselected from the group consisting of a thickening agent, a pH adjuster,one or more surfactant, emulsifying agents, and an anti-oxidant. In someembodiments, the thickening agent is selected from the group consistingof acritamers, carbomers or pemulens. In some embodiments the thickeningagent comprises a carbomer. More than one thickening agent can be used.In some embodiments the pH adjuster comprises a base such as, forexample, trolamine (also known as triethanolamine). More than one pHadjuster can be used. In some embodiments the surfactant may be selectedfrom a polysorbate (e.g., polysorbate 20). In some embodiments thesurfactant may also act as an emulsifying agent, and more than oneemulsifying agent may also be used. In some embodiments, theanti-oxidant is butylated hydroxytoluene (BHT). More than oneanti-oxidant can be used. In some embodiments, the pH adjuster may alsohave surfactant properties such as, for example, triethanolamine.

In another aspect, the disclosure relates to a composition comprising5,5′-dimethyl-2,2′-dipyridyl in an amount from about 0.25% to about 5%by weight; benzyl alcohol in an amount from about 0.5% to about 10% byweight; mineral oil in an amount from about 2% to about 35% by weight;water in an amount from about 35% to about 95% by weight; carbomer in anamount from about 0.1% to about 1% by weight; trolamine in an amountfrom about 0.1% to about 2% by weight; and polysorbate 20 in an amountfrom about 0.1% to about 5% by weight. In some embodiments of thisaspect the 5,5′-dimethyl-2,2′-dipyridyl may be present in an amount fromabout 0.5% to about 1% by weight; the benzyl alcohol may be present inan amount from about 1% to about 3% by weight; the mineral oil may bepresent in an amount from about 20% to about 30% by weight; the watermay be present in an amount from about 60% to about 90% by weight; thecarbomer may be present in an amount from about 0.1% to about 0.5% byweight; the trolamine may be present in an amount from about 0.1% toabout 1% by weight; and the polysorbate 20 may be present in an amountfrom about 0.5% to about 2% by weight.

In further embodiments of this aspect, the composition can be formulatedas a lotion, a cream, an emulsion, a foam or a gel and may compriseabout 0.74% by weight 5,5′-dimethyl-2,2′-dipyridyl; and/or about 24% byweight mineral oil; and/or about 1% by weight polysorbate 20; and/orabout 2% by weight benzyl alcohol.

In some embodiments the composition comprises 2% by weight benzylalcohol, 24% mineral oil, 1% polysorbate 20 and 0.74%,5,5′-dimethyl-2,2′-dipyridyl and said composition exhibits a greaterlousicidal activity than a similar composition that does not comprise5,5′-dimethyl 2,2′-dipyridyl.

In further embodiments the composition comprises 2% by weight benzylalcohol, 24% mineral oil, 1% polysorbate 20 and 0.74%,5,5′-dimethyl-2,2′-dipyridyl and said composition exhibits a greaterovicidal activity than a similar composition that does not comprise5,5′-dimethyl 2,2′-dipyridyl.

In another aspect, the disclosure provides an aqueous composition fortopical application to a subject comprising by weight: 0.74%5,5′-dimethyl-2,2′-dipyridyl; 24% mineral oil; 2.00% benzyl alcohol,0.15% Carbomer; 0.2% Trolamine; 1% polysorbate 20, 0.5% BHT and thebalance purified water.

In a further aspect the disclosure relates to a method of treating alice infestation, the method comprising topically applying to a hosthaving a lice infestation an effective amount of a composition accordingto the various aspects and embodiments described herein. In embodiments,the method may kill lice and inhibit lice eggs from hatching. In furtherembodiments, the method may kill more lice and inhibit eggs fromhatching relative to a vehicle composition comprising the samecomponents except for 5,5′-dimethyl-2,2′-dipyridyl.

Other embodiments of the invention provide methods of treating pestinfestation comprising administering to a subject in need thereof, atherapeutically effective amount of the pediculicidal compositionsdisclosed herein.

The disclosure provides for other aspects and embodiments that will beapparent in view of the description that follows.

DETAILED DESCRIPTION

In an aspect, the invention provides a pediculicidal compositionformulation. The pediculicidal composition comprises a metal chelatingagent, an activating solvent system, and a carrier vehicle. In aspecific embodiment, the pediculicidal composition comprises5,5′-dimethyl-2,2′-dipyridyl, an oil phase comprising an activatingsolvent system, and an aqueous phase which combines with the oil phaseto form a carrier vehicle. The inventors have identified that anactivating solvent system can provide for increases in the pediculicidalactivity of the compositions disclosed herein. Further, the inventorshave identified the amount of surfactant included in the compositionscan have an unexpected effect on the pediculicidal activity of thecompositions disclosed herein.

The term “pediculicidal composition” is used herein to refer to acomposition with a metal chelating agent that exhibits ovicidal andlousicidal activity against lice eggs and lice, respectively.

One of skill in the art will appreciate that any of the recited numericranges referred to herein (e.g., weight percent ranges) regarding any ofthe components of the compositions can encompass all weight percentvalues falling within those ranges (e.g., “about 1% to about 10%”includes about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% as well asincluding fractions of those weight percent values (e.g., 5.1%, 5.2%,5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, and 5.9%) as well as sub-rangeswithin the broader range (e.g., “about 1% to about 10%” includes about2% to about 8%, about 3% to about 6%, and about 6% to about 10%). Theseare just examples of the ranges and values falling within the scope ofthe identified ranges in the disclosure.

The term “metal chelating agent” as used herein refers to a compoundcomprising at least two heteroatoms able to simultaneously coordinatewith a metal ion, at least one of the two heteroatoms being selectedfrom nitrogen, sulphur, oxygen and phosphorus, wherein the compoundcomprises at least one carbocyclic ring substituted with at least oneheteroatom and/or with a substituent containing at least one heteroatom,or the compound comprises at least one heterocyclic ring containing atleast one heteroatom, wherein said heterocyclic ring is optionallysubstituted with at least one heteroatom and/or with a substituentcontaining at least one heteroatom.

Preferred metal chelating agents include, but are not limited to:6,6′-dimethyl-2,2′-dipyridyl, 5,5′-dimethyl-2,2′-dipyridyl,4,4′-dimethyl-2,2′-dipyridyl or a pharmaceutically, veterinary oragriculturally acceptable salt thereof, preferably5,5′-dimethyl-2,2′-dipyridyl.

In some embodiments, the pediculicidal composition comprises a metalchelating agent at a concentration preferably from about 0.25% orgreater, preferably between from about 0.25% to about 5% by weight, morepreferably between from about 0.25% to about 1% by weight. Specifically,a preferred composition comprises at least 0.25% or greaterconcentration of 5,5′-dimethyl-2,2′-dipyridyl. In some embodiments thecomposition comprises about 5%, 4.75%, 4.50%, 4.25%, 4.0%, 3.75%, 3.50%,3.25%, 3.0%, 2.75%, 2.50%, 2.25%, 2.0%, 1.75%, 1.50%, 1.25%, 1.0%,0.75%, 0.50%, or about 0.25% concentration of5,5′-dimethyl-2,2′-dipyridyl. In specific embodiments, this component ispresent in a concentration of approximately 0.37% to about 0.9%, whichrange is inclusive of illustrative embodiments as described in theExamples (e.g., about 0.9%, 0.74%, 0.55%, 0.54%, 0.38%, and 0.37%).

The term “activating solvent system” as used herein refers to a mixturehaving at least a solvent and a co-solvent. As described herein, and asillustrated in the Examples, some embodiments of the disclosure providean activating solvent system that provides for superior enhancement ofthe lousicidal and ovicidal activity of 5,5′-dimethyl-2,2′-dipyridyl ina pediculicidal composition. It is of note that the pediculicidalcomposition is one that exhibits both ovicidal and lousicidal activity.In some embodiments, an activating solvent system comprising an alcoholand a hydrocarbon provides for a composition that possesses unexpectedovicidal, lousicidal, and/or pediculicidal activity, as compared tosimilar compositions that lack one or more features of the activatingsolvent system. For example, an activating solvent system that preservesboth the alcohol and the hydrocarbon combines to produce the unexpectedand beneficial improvements in ovicidal, lousicidal, and/orpediculicidal activity.

In some embodiments, the pediculicidal composition comprises anactivating solvent system at a concentration preferably from about 2% toabout 85% by weight, preferably between from about 2% to about 55% byweight, more preferably from between about 2% to about 35% by weight. Aparticularly preferred activating solvent system, in some embodiments,is a combination of an alcohol and hydrocarbon, and in more specificembodiments, a preferred alcohol is selected from phenoxyethanol andbenzyl alcohol, and a preferred hydrocarbon is mineral oil. In someembodiments the alcohol is benzyl alcohol and the hydrocarbon is mineraloil.

The term “solvent” as used herein refers to a liquid that is capable ofdissolving the metal chelating agent. In some embodiments, the preferredsolvent includes, but is not limited to: alcohols, heterocycliccompounds, alkoxylated alcohol, esters, thio compounds, hydrocarbons,fats and oils.

In some further embodiments, the preferred solvents include, but are notlimited to: ethanol, octyldodecanol, benzyl alcohol, phenoxyethanol,methyl pyrrolidone, polyethylene glycol 300, PPG-15 stearyl ether,diisopropyl adipate, propylene glycol caprylate, propylene glycoldicaprylate, isopropyl myristate, dimethyl sulfoxide, limonene,caprylic/capric triglyceride and peanut oil.

In yet further embodiments, the preferred solvent is a mixture ofsolvents selected from the group consisting of ethanol, octyldodecanol,benzyl alcohol, phenoxyethanol, methyl pyrrolidone, polyethylene glycol300, PPG-15 stearyl ether, diisopropyl adipate, propylene glycolcaprylate, propylene glycol dicaprylate, isopropyl myristate, dimethylsulfoxide, limonene, caprylic/capric triglyceride and peanut oil.

In some embodiments, the preferred solvent is an alcohol. In a furtherembodiment, the solvent is ethanol, octyldodecanol, benzyl alcohol orphenoxyethanol, preferably benzyl alcohol. In yet a further embodimentthe solvent is a mixture of ethanol, octyldodecanol, benzyl alcohol orphenoxyethanol.

In some embodiments, the pediculicidal composition comprises a solventat a concentration from about 0.5% to about 35% by weight, preferablyfrom about 0.5% to about 10% by weight.

The term “co-solvent” as used herein refers to a liquid that is misciblewith the solvent. In some embodiments, the preferred co-solvent is ahydrocarbon or ester. In a further embodiment, the co-solvent is mineraloil or caprylic/capric triglycerides, preferably mineral oil.

In some embodiments, the preferred pediculicidal composition comprises aco-solvent at a concentration from about 2% to about 50% by weight,preferably from about 2% to about 35% by weight.

The solvent and co-solvent can be mixed with the metal chelating agentin any order. For example, in some embodiments, the metal chelatingagent is dissolved by the solvent, followed by addition of theco-solvent. In other embodiments the metal chelating agent is dissolvedin the co-solvent, followed by the addition of the solvent. In yet otherembodiments, the metal chelating agent is dissolved by a mixture of thesolvent and co-solvent, or by the solvent and co-solvent being added tothe metal chelating agent at about the same time.

The term “carrier vehicle” as used herein refers to a solution, anemulsion, a gel, an ointment, a spray, a foam or a mixture thereof thatmay comprise water, the activating solvent system, and at least oneagent selected from the group consisting of a thickening agent, a pHadjuster, one or more emulsifying agents, and an anti-oxidant, anemulsifier and an emulsion stabilizer or a mixture thereof. In someembodiments, the carrier vehicle may be a clear, single-phase liquid, awater-in-oil emulsion, an oil-in-water emulsion, a mixed emulsion, alotion, a cream, an aqueous gel, a non-aqueous gel, a hydrophobicointment, a hydrophilic ointment, an aerosol spray, a non-aerosol spray,an aerosol foam, a non-aerosol foam or a mixture thereof. In a furtherembodiment, the carrier vehicle is an aqueous gel or lotion comprisingwater, an activating solvent system and at least one agent selected fromthe group consisting of a thickening agent, a pH adjuster, one or moreemulsifying agents and an anti-oxidant, or a mixture thereof.

In some embodiments, the pediculicidal composition comprises a carriervehicle having water at a concentration of about 15% to about 98% byweight, preferably from about 35% to about 95% by weight.

The term “thickening agent” as used herein refers to a substance that iscapable of changing the viscosity of the carrier vehicle. In someembodiments, the preferred thickening agent includes, but is not limitedto: agar, acrylic acid polymers and copolymers, alginates and salts andderivatives thereof, carrageenan, chitosan, cellulose derivatives,dextrin, gelatin, gum, gum derivatives, maltodextrin, pectin,polycarbophil, polydextrose, polyethylene glycol (PEG), polyethyleneoxide, poly(methyl vinyl ether/maleic anhydride) and copolymers andderivatives thereof, polyvinyl alcohol, polyvinylpyrrolidone (PVP),pregelatinized starch, hyaluronan, sulfobutylether beta-cyclodextrin ormixtures thereof.

In further embodiments, the preferred thickening agent includes, but isnot limited to: agar, acritamers, carbomers, pemulens (amine salt,ammonium salt, sodium salt, potassium salt of these polymers), propyleneglycol alginate, kappa (sodium salt), iota (sodium salt), lambda,chitosan, hydroxyethyl cellulose, hydroxyethyl methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose,sodium carboxymethylcellulose, dextrin, gelatin, acacia, ceratonia,guar, tragacanth, xanthan gum, hydroxypropyl guar, guarhydroxypropyltrimonium chloride, maltodextrin, pectin, polycarbophil,polydextrose, PEG 200, PEG 300, PEG 400, PEG 540, PEG 600, PEG 900, PEG1000, PEG 1450, PEG 1500, PEG 1540, PEG 2000, PEG 3000, PEG 3350, PEG4000, PEG 4600, PEG 6000, PEG 8000, PEG 20000, PEG 35000, polyethyleneoxide, poly(methyl vinyl ether/maleic anhydride) and copolymers andderivatives thereof, polyvinyl alcohol, PVP K12, PVP K15, PVP K17, PVPK25, PVP K30, PVP K60, PVP K90, PVP K120, pregelatinized starch,hyaluronic acid, sodium hyaluronate, sulfobutylether beta-cyclodextrin,trehalose or mixtures thereof.

In yet another embodiment, the preferred thickening agent includes, butis not limited to: propylene glycol alginate, cellulose derivatives,acrylic acid polymers and copolymers or mixtures thereof. In yet anotherembodiment, the preferred thickening agent includes, but is not limitedto: propylene glycol alginate, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose, sodium carboxymethylcellulose, acritamers, carbomers,pemulens or mixtures thereof. In some embodiments, the thickening agentis carbomer.

In some embodiments, the preferred pediculicidal composition comprises athickening agent at a concentration from about 0.01% to about 2% byweight, preferably from about 0.1% to about 1% by weight. In someembodiments, more than one thickening agent is used.

The term “emulsifying agent” as used herein refers to a substance thatacts as an emulsifier, an emulsion stabilizer or a surfactant. The term“emulsifier” as used herein refers to a substance that aids thedispersion of one liquid in another liquid. In some embodiments, thepreferred emulsifier includes, but is not limited to: glycerine, gum,laurate esters, lecithin, polyoxyethylene ether, polyoxyethylene diols,polyvinyl carboxy polymer, polyol, triyglycerol ester, stearic acid,sorbitan stearate or mixtures thereof. In some embodiments, theemulsifier is polyoxyl-40 stearate.

In some embodiments, the preferred pediculicidal composition comprisesan emulsifier at a concentration from about 0.1% to about 5% by weight,preferably from about 1% to about 5% by weight. In some embodiments,more than one emulsifier may be used.

The term “emulsion stabilizer” as used herein refers to a substance thataids in the stabilisation of an emulsion. In some embodiments, thepreferred emulsion stabilizer includes, but is not limited to: analcohol, acetic acid, carbomer, gum palmitic acid, polyethylene glycol,isostearic acid, stearic acid, or mixtures thereof.

In some embodiments, the preferred emulsion stabilizer is an alcohol. Ina further embodiment, the preferred emulsion stabilizer is cetylalcohol, stearyl alcohol or a mixture thereof.

In some embodiments, the preferred pediculicidal composition comprisesan emulsion stabilizer at a concentration from about 0.1% to about 10%by weight, preferably from about 1% to about 6% by weight.

The term “surfactant” as used herein refers to an agent that lowers thesurface tension between two liquids, for example between an aqueoussolution and an oil. In some embodiments, the surfactant comprises anon-ionic surfactant, an anionic surfactant, a cationic surfactant or amixture thereof. In further embodiments, the surfactant includes, but isnot limited to: sodium docusate, sodium lauryl sulphate, sodium laurethsulphate, benzethonium chloride, cetrimide, cetylpyridinium chlorideethoxylated carboxylic acids such as PEG-8 stearate, PEG-12 stearate,PEG-20 stearate, PEG-30 stearate, PEG-40 stearate, PEG-50 stearate,PEG-100 stearate, PEG-12 distearate, PEG-32 distearate, PEG-150distearate and PEG-10 oleate; ethoxylated glycerides such as PEG-35castor oil, PEG-40 hydrogenated castor oil and PEG-60 hydrogenatedcastor oil; polyhydric alcohol esters and ethers, such as methylgluceth-20 sesquistearate; ethoxylated sorbitan esters such aspolysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80;ethoxylated alcohols such as ceteareth-6, ceteareth-12, ceteareth-20,ceteareth-25, ceteth-10, ceteth-20, laureth-4, laureth-5, laureth-9,laureth-10, laureth-12, laureth-15, laureth-20, laureth-23, oleth-10,oleth-20, steareth-10, steareth-20 and steareth-100; ethoxylated lanolinsuch as PEG-20 lanolin, PEG-30 lanolin, PEG-75 lanolin, PEG-100 lanolinand PEG-150 lanolin; ethoxylated polysiloxanes such as dimethiconecopolyol; propoxylated POE ethers such as poloxamer 124, poloxamer 188,poloxamer 237, poloxamer 338 and poloxamer 407; and alkylpolyglucosidessuch as caprylyl glucoside, decyl glucoside, lauryl glucoside,coco-glucoside, cetearyl glucoside and isostearyl glucoside or mixturesthereof.

In some embodiments, the surfactant comprises alkylpolyglucoside. In afurther embodiment, the surfactant includes, but is not limited to:caprylyl glucoside, decyl polyglucoside, lauryl glucoside,coco-glucoside, cetearyl glucoside and isostearyl glucoside or mixturesthereof. In yet a further embodiment, the surfactant comprises decylpolyglucoside.

In some embodiments, the surfactant is an ethoxylated alcohol. In afurther embodiment the surfactant includes, but is not limited to:ceteareth-6, ceteareth-12, ceteareth-20, ceteareth-25, ceteth-10,ceteth-20, laureth-4, laureth-5, laureth-9, laureth-10, laureth-12,laureth-15, laureth-20, laureth-23, sodium laureth sulphate oleth-10,oleth-20, steareth-10, steareth-20, steareth-100 or mixtures thereof. Inyet a further embodiment the surfactant comprises sodium laurethsulphate.

In some embodiments, the surfactant comprises an ethoxylated sorbitanester. In a further embodiment the surfactant includes, but is notlimited to: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80 or mixtures thereof. In yet a further embodiment, the surfactantcomprises polysorbate 20. In some embodiments, the surfactant also actsas an emulsifier. For example, polysorbate 20 acts as a surfactant andan emulsifier. In some embodiments, more than one surfactant is used.

In some embodiments, the pediculicidal composition comprises asurfactant at a concentration from about 0.1% to about 10% by weight,preferably between 0.1% to about 5% by weight. In specific embodiments,a particularly preferred composition comprises polysorbate 20,preferably at a concentration of about 1% to about 5% (w/w), aconcentration of about 1% and less than 5%, and more preferably at aconcentration of about 1% w/w. Some of the illustrative embodimentsprovided in the Examples demonstrate an unexpected effect relating tocompositions that comprise about 1% w/w of surfactant. These effects maybe beneficially observed with the combination of the surfactant with theactivating solvent system; however is should be noted that a benefit maybe seen with just the activating solvent system alone, or just thesurfactant alone, although a composition comprising both components ispreferred.

The term “pH adjuster” as used herein refers to a substance that iscapable of raising or lowering pH levels. In some embodiments, the pHadjuster comprises a base. In a further embodiment, the pH adjusterincludes, but is not limited to: bicarbonates, carbonates, amines,alkanolamines, hydroxides, alkaline earth metal hydroxides, transitionmetal hydroxides or a mixture thereof. In yet a further embodiment, thepH adjuster includes, but is not limited to: potassium hydroxide orsodium hydroxide. In another embodiment, the pH adjuster comprisestriethanolamine. In some embodiments, the pH adjuster can also be asurfactant, for example triethanolamine acts as a pH adjuster and asurfactant.

In some embodiments, the pH adjuster comprises an acid, an acid salt, ora mixture thereof.

In some embodiments, the pH adjuster comprises a buffer. In a furtherembodiment the buffer includes, but is not limited to: a citrate/citricacid, acetate/acetic acid, phosphate/phosphoric acid, formate/formicacid, propionate/propionic acid, lactate/lactic acid, carbonate/carbonicacid, ammonium/ammonia, edentate/edetic acid, or mixtures thereof.

In some embodiments, the preferred pediculicidal composition comprises apH adjuster in an amount sufficient to adjust the pH of the compositionto a pH of between about 3 to about 9, preferably in an amountsufficient to adjust the pH of the composition to a pH of between about5 to about 9, more preferably in an amount sufficient to adjust the pHof the composition to a pH of between about 5 to about 7.5.

In some embodiments, the preferred pediculicidal composition comprises apH adjuster at a concentration from about 0.1% to about 5% by weight,preferably from about 0.1% to about 2% by weight. In some embodiments,more than one pH adjuster is used.

The term “anti-oxidant” as used herein refers to an agent that preventsthe oxidative degradation of, or preserves, the other ingredients of thepediculicidal composition. The antioxidant may comprise, or may beselected from the group consisting of, amino acids (e.g. glycine,histidine, tyrosine, tryptophan) and their derivatives, imidazoles,(e.g. urocanic acid) and their derivatives, peptides, such asD,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g.anserine), carotenoids, carotenes (e.g. α-carotene, β-carotene,lycopene) and their derivatives, chlorogenic acid and derivativesthereof, lipoic acid and its derivatives (e.g. dihydrolipoic acid),aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin,glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl,methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl,γ-linoleyl, cholesteryl and glyceryl esters) and their salts, dilaurylthiodipropionate, distearyl thiodipropionate, thiodipropionic acid andits derivatives (esters, ethers, peptides, lipids, nucleotides,nucleosides and salts) and sulfoximine compounds (e.g. buthioninesulfoximines, homocysteine sulfoximine, buthionine sulfones, penta-,hexa-, heptathionine sulfoximine), typically in very low tolerated doses(e.g. pmol to μmol/kg), and also chelating agents (e.g. α-hydroxy fattyacids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (e.g.citric acid, lactic acid, malic acid), humic acid, bile acid, bileextracts, bilirubin, biliverdin, ethylenediaminetetraacetic acid (EDTA),ethylene glycol tetraacetic acid (EGTA) and their derivatives,unsaturated fatty acids and their derivatives (e.g. γ-linolenic acid,linoleic acid, oleic acid), folic acid and its derivatives, ubiquinoneand ubiquinol and derivatives thereof, vitamin C and its derivatives(e.g. ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate),tocopherols and derivatives (e.g. vitamin E acetate), vitamin A andderivatives (vitamin A palmitate) and coniferyl benzoate of benzoinresin, rutinic acid and its derivatives, α-glucosylnitin, ferulic acid,furfurylideneglucitol, carnosine, butylhydroxytoluene (BHT),butylhydroxyanisole (BHA), nordihydroguaiacic acid, nordihydroguaiareticacid, trihydroxybutyrophenone, uric acid and its derivatives, mannoseand its derivatives, zinc and its derivatives (e.g. ZnO, ZnSO₄),selenium and its derivatives (e.g. selenomethionine), stilbenes andtheir derivatives (e.g. stilbene oxide, trans-stilbene oxide), vitaminA, vitamin B2, vitamin B6, vitamin B9 (folic acid), vitamin B12, vitaminC, vitamin E, selenium, carotenes (β-carotene, lutein, zeaxanthin, andlycopene), zinc, copper, proanthocyanidins (e.g. anthocyanidins,flavonols [e.g. catechins, epicatechins, procyanidins], flavanones,flavonols), nac n-acetylcysteine, α-lipoic acid, coenzyme Q10, ginkgobiloba, green tea extract, isothiocyanates (e.g. sulforaphane), phenols(e.g. caffeic acid, and ferulic acid), olive oil, sulfides/thiols (e.g.diallyl sulfide, allyl methyl trisulfide, and dithiolthiones),lycopenes, and the derivatives (salts, esters, ethers, sugars,nucleotides, nucleosides, peptides and lipids) of said activeingredients.

In certain embodiments, the antioxidant may be selected from anantioxidant that is used in, or is approved for use in, pharmaceuticalformulations. In some embodiments, the antioxidant may be selected froman antioxidant that is used, or is approved for use in a topicalformulation. In the above embodiments, the antioxidant can be includedup to, and including, the maximum allowable concentration that isapproved for pharmaceutical applications and uses (e.g., topicalapplication/use). In some embodiments the antioxidant can comprise, orbe selected from the group consisting of, ascorbic acid, ascorbylpalmitate, BHA, BHT, EDTA, olive oil, propyl gallate, sodiummetabisulfite, sodium metabisulfite, sodium sulfite, and tocopherol.

In some embodiments, the antioxidant is selected from BHA, BHT, or amixture thereof. In further embodiments, the antioxidant is BHT.

The total amount of antioxidants (one or more compounds) in thecompositions, when present, can be in an amount of from about 0.001 wt.% to about 30 wt. %, or from about 0.05 wt. % to about 20 wt. %, orabout 1 wt. % to about 10 wt. %. The concentration of the antioxidantmay be determined by one of skill in the art, and can vary in relativelybroad ranges such as, for example, about 0.001 wt. % to about 10%, suchas about 0.001 wt. % to about 5 wt. %, or about 0.001 wt. % to about 3wt. %, or about 0.001 wt. % to about 1 wt. % or about 0.001 wt. % toabout 0.1 wt. %, or about 0.001 wt. % to about 0.01 wt. %.

In another non-limiting embodiment, a pediculicidal composition thatcomprises BHT as an antioxidant, the BHT may be present at aconcentration ranging between about 0.001 wt. % to about 10%, such asabout 1 wt. % to about 10 wt. % or about 1 wt. % to about 5 wt. %, orabout 1 wt. % to about 3 wt. %, or about 2 wt. %. In some embodiments,more than one antioxidant may be used.

The compounds of the invention may be in the form of pharmaceutically,veterinary or agriculturally acceptable salts.

A number of metal chelating agents and other compounds mentioned usefulin the present invention can be obtained commercially from specialitychemical companies. Those not commercially available can be synthesizedfrom commercially available starting materials using reactions known tothose skilled in the art.

Another aspect of the invention is providing a method of treating ahuman head lice infestation comprising administering to a subject inneed thereof, a therapeutically effective amount of a pediculicidalcomposition substantially as described herein below.

In some embodiments, a pediculicidal composition according to thepresent invention may be applied to the hair or skin of a subject inneed thereof. The pediculicidal composition may be applied topically inthe form of a solution, cream, emulsion, lotion, gel, spray, ointment orfoam. In some embodiments, the composition can be prepared as amedicament for preventing or treating lice infestation. As discussedherein, embodiments provide for the use of the disclosed composition ina medicament that comprises one or more other active agents that mayhave ovicidal (kills eggs), lousicidal (kills lice), or pediculicidal(kills both eggs and lice) activity or efficacy.

To the extent that the disclosure relates to treatment with certaincompositions, it should be understood that the disclosure alsoparticularly contemplates use of the compositions described herein forthe treatment of a pest infestation on a host. Also contemplated areuses in the topical treatment of a lice infestation on a host. In someof the above embodiments, the use of the composition kills lice. In someof the above embodiments, the use of the composition inhibits egghatching. In some of the above embodiments, the use of the compositionkills lice and inhibits egg hatching. In these embodiments, thecomposition on the host kills more lice when compared to a vehiclecomposition that does not include 5,5′-dimethyl-2,2′-dipyridyl, butotherwise includes the same components.

The terms “administering” and “administration” are used herein to meanany method which delivers the composition to a subject in such a manneras to provide the desired ovicidal, lousicidal or pediculicidal activityor efficacy. In some embodiments the administering comprises contactingthe subject (e.g., topical application) with the composition. In someembodiments the administering comprises contacting or application of thecomposition to the skin, hair, or both skin and hair of the subject.

The term “pediculicidal efficacy” is used herein to refer to the abilityof a composition with a metal chelating agent to treat a liceinfestation and thus be effective in preventing lice eggs from hatchingand effective to kill lice.

The terms “effective amount,” “an amount effective to,” or a“therapeutically effective amount” are used herein to refer to an amountof the pediculicidal composition sufficient to provide treatment orprevention of lice infestation in a human, or otherwise control aninfestation. The effective amount of a pediculicidal composition mayvary depending on the host and the type and level of infestation. In oneembodiment, the pediculicidal composition is applied to the scalp orinto the hair of a person suffering from head lice infestation and isleft on the treated person for a period of time. Preferably the periodof time is about 10 minutes. In embodiments the period of time is fromabout 10 minutes to about 120 minutes, about 10 minutes to about 60minutes, about 10 minutes to about 50 minutes, about 10 minutes to about40 minutes, about 10 minutes to about 30 minutes, or about 10 minutes toabout 20 minutes. In a further embodiment, the pediculicidal compositionis washed off the hair or scalp of a person with warm or cold water.

In another embodiment, the pediculicidal composition may be used as partof a regimen for the treatment of a disease, disorder or condition ofthe skin. The pediculicidal composition may be used in combination witha separate pharmaceutical dosage form. In some embodiments for example,the pediculicidal composition of the invention may be used incombination with another lousicidal or ovicidal composition. Suchcompositions are known to those of skill in the art may includecompositions such as compositions containing permethrin, malathion,ivermectin, spinosad or phenothrin and/or in combination withnon-chemical head lice and nits treatments or the use of wet combing.

Throughout this specification the word “comprise,” or variations such as“comprises” or “comprising,” will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

The invention will hereinafter be described by way of the followingnon-limiting Examples.

EXAMPLES Example 1. Manufacture of a Pediculicidal Composition (0.74%w/w Formulation of Table 1)

5,5′-dimethyl-2,2′-dipyridyl, benzyl alcohol (solvent), light mineraloil (co-solvent), Polysorbate 20 (surfactant) and BHT (anti-oxidant) areadded to a vessel, heated to 55±2° C. and mixed using a propeller mixeruntil completely dissolved. The clear solution is cooled to 35° C. orless under propeller mixer. Carbopol 980 (thickening agent) is added andmixed until completely dispersed. The mixture is transferred into atank.

Purified water is added to the original vessel, stirred, transferred tothe tank and mixed until homogenous using the propeller mixer. Trolamineis added and mixed until homogenous using the propeller mixer. The pH ofthe solution is measured while mixing, adjusted with additionaltrolamine to reach a pH of 6.5-7.5 and then mixed for a total of 60minutes, after which time the pH is verified and adjusted to pH 6.5-7.5with additional trolamine, if required.

TABLE 1 Formulation of 0.74% w/w 5,5′-dimethyl-2,2′-dipyridyl lotionQuantity Quantity Material % w/w (kg) Function Oil phase 5,5′-dimethyl2,2′-dipyridyl 0.74 0.296 Active ingredient Light mineral oil 24.00 9.6co-solvent Benzyl Alcohol 2.00 0.8 solvent Polysorbate 20 1.00 0.4surfactant Butylated hydroxytoluene 0.50 0.2 anti-oxidant Total oilphase 28.24 11.296 Aqueous phase Purified water USP 71.41 28.564Carbopol 980 0.15 0.06 Thickening agent Trolamine 0.20 0.08 pHadjuster/surfactant Trolamine QS pH adjuster Total aqueous phase 71.7628.784 Total 100.00 40.00

Example 2. Manufacture of a Pediculicidal Composition (0.74% Formulationof Table 6 and Table 7)

Oil phase: 5,5′-dimethyl-2,2′-dipyridyl, benzyl alcohol (solvent),mineral oil (co-solvent), and polysorbate 20 (surfactant) are added to avessel and are mixed until a clear solution is obtained. The mixture canbe heated to 50-60° C. to facilitate the dissolution of the components.The clear solution is cooled to below 30° C.

Water phase: Purified water is added to a separate vessel and stirred.While stirring, carbomer (thickening agent) is added slowly. Thestirring is continued until the carbomer is fully hydrated.

Emulsification: The water phase is stirred and the oil phase is added tothe water phase. Stirring is continued to ensure the oil phase isuniformly dispersed in the water phase. Stirring is continued andtrolamine is added. The mixture is stirred until homogenous. The pH ofthe mixture is in the range from 6.7 to 7.3.

Example 3. Effect of Formulated 5,5′-Dimethyl-2,2′-Dipyridyl on EggHatching in Pediculus humanus capitis

Gravid female lice were permitted to lay eggs over a 24 hour period. Theeggs were counted, inspected under a light microscope and all eggs thatappeared undamaged were allocated to one of two treatment groups. Onegroup of 10 eggs was exposed to 5,5′-dimethyl-2,2′-dipyridyl in aformulation (52-06-01), while the second group of 10 eggs was exposed tothe formulation only (vehicle, 52-06-02) Table 2. The two formulationswere as follows:

TABLE 2 Component 52-06-01 52-06-02 5,5′-dimethyl-2,2′-dipyridyl  0.38% 0.00% Octyldodecanol  11.9%  12.0% Capric/Caprylic Triglycerides  37.7% 38.0% Sodium Lauryl Ether Sulphate  6.0%  6.0% (70%) Cetyl Alcohol 1.2%  1.2% Stearyl Alcohol  1.2%  1.2% Glyceryl Monostearate  1.2% 1.2% PEG-40 Stearate  2.4%  2.4% Water  36.8%  36.7% Benzyl Alcohol 0.99%  1.0% Butylated Hydroxy Toluene 0.098% 0.099% PotassiumDihydrogen 0.050% 0.050% phosphate Dipotassium Hydrogen  0.15%  0.15%phosphate

The protocol was as follows:

Treatments:

Following a 10 minute exposure to either the 52-06-01 or 56-06-02formulations the eggs were subsequently washed for 1 minute with water(˜37° C.) before being placed at 31° C. in a humid incubator andmonitored over time for signs of development specifically of the eyesand through to subsequent hatching.

Results: The results (summarised in Table 3) indicate that a 0.37% w/wformulation of 5,5′-dimethyl-2,2′-dipyridyl can significantly supressegg hatching in head lice. Out of a total of ten eggs treated with theformulation containing 5,5′-dimethyl-2,2′-dipyridyl, two of the eggsdeveloped, but only one of these eggs hatched. Overall, 90% of the eggsin the treatment arm failed to hatch. In the vehicle treated group, onlyone egg failed to develop, of the remaining eggs, 60% of the eggsactually hatched, and 30% developed into nymphs but did not hatch. Thisdata shows that a formulation containing 5,5′-dimethyl-2,2′-dipyridylwith an activating solvent system and surfactant can significantlyinhibit head lice eggs from hatching compared to vehicle.

TABLE 3 Treatment 5,5′-dimethy1-2,2′-dipyridyl Vehicle Day 1 ofobservation Stage of development 1 eye development 0 eye development 9no eye development Day 4 Stage of development 1 hatched 4 eyedevelopment 1 eye development 6 no eye development 8 no eye developmentDay 5 Stage of development 1 hatched 8 eye development 1 eye development2 no eye development 8 no eye development Day 6 Stage of development 1hatched 9 eye development 1 eye development 1 no eye development 8 noeye development Day 7 Stage of development 1 hatched 5 hatched 1 eyedevelopment 4 eye development 8 no eye development 1 no eye developmentDay 12 Stage of development 1 hatched 6 hatched 1 eye development 3 eyedevelopment 8 no eye development 1 no eye development

Example 4. Evaluation of Pediculicidal Efficacy of Compositions AgainstPediculus humanus humanus

TABLE 4 5,5′-dimethyl-2,2′-dipyridyl compositions 07-08-04 11-08-1411-08-13 27-08-02 26-08-10 26-08-04 Quantity Quantity Quantity QuantityQuantity Quantity Component (Function) (% w/w) (% w/w) (% w/w) (% w/w)(% w/w) (% w/w) 5,5′-dimethyl-2,2′-dipyridyl 0.37 0.37 0.37 0.55 0.740.00 (Metal chelating agent) Octyldodecanol 12.00  12.00  — — — —(Solvent/co-solvent) Caprylic/capric Triglycerides 17.50  17.50  — — — —(solvent/co-solvent) Mineral Oil — — 5.00 5.00 5.00 5.00 (Co-solvent)Cetyl Alcohol 2.40 — — — — — (Emulsion Stabilizer) Stearyl Alcohol 2.40— — — — — (Emulsion Stabilizer) Carbomer 1342 — 1.00 — — — — (Thickeningagent) Carbomer — — 0.30 0.30 0.30 0.30 (Thickening agent)Triethanolamine — 1.10 0.35 0.35 0.35 0.35 (pH Adjuster) GlycerylMonostearate 2.40 — — — — — (Emulsifier) Polyoxyl-40 Stearate 4.80 — — —— — (Emulsifier) Benzyl Alcohol 1.00 5.00 2.00 2.00 2.00 2.00(Solvent/preservative) Sodium laureth sulfate-70% 6.00 6.00 — — — —(surfactant) Polysorbate 20 — — 1.00 1.00 1.00 1.00 (surfactant)Monobasic Potassium Phosphate 0.04 — — — — — (pH Adjuster) DibasicPotassium Phosphate 0.16 — — — — — (pH Adjuster) Purified Water 50.93 57.03  90.98  90.80  90.61  91.35  (Aqueous solvent) Total 100.00 100.00  100.00  100.00  100.00  100.00 

The above formulations (Table 4) were prepared and assessed forpediculicidal efficacy. Each composition comprises5,5′-dimethyl-2,2′-dipyridyl and the carrier vehicle comprising asolvent system containing a solvent and a co-solvent, water and otheringredients such as one or more emulsifying agents, a thickening agentand pH adjuster which together are formulated as a lotion, cream, foamor a gel. The pediculicidal efficacy was determined by measuring theovicidal activity (Eggs/% Hatch), and the lousicidal activity (Lice/%Mortality) of each composition. A low percentage, such as between 0% andabout 10% of lice eggs hatching, indicates that a composition has goodovicidal activity. A high percentage of dead lice, such as between about85% and 100% mortality, indicates that a composition has good lousicidalactivity. The compositions that exhibit good ovicidal activity and goodlousicidal activity are pediculicidal compositions. The results of thepediculicidal efficacy study are shown in Table 5.

TABLE 5 Efficacy of 5,5′-dimethyl-2,2′-dipyridyl compositions asovicides (Eggs/% Hatch) and lousicides (Lice/% Mortality) Lice/% Eggs/%Mortality Product Hatch (17 hrs) 0.37% w/w 5,5′-dimethyl-2,2′- 2 1dipyridyl lotion Formula 07-08-04 0.9% w/w 5,5′-dimethyl-2,2′- Notdetermined 25 dipyridyl lotion Formula 48-06-01 0.37% w/w5,5′-dimethyl-2,2′- 0 11 dipyridyl lotion Formula 11-08-14 0.37% w/w5,5′-dimethyl-2,2′- 0 46 dipyridyl lotion Formula 11-08-13 0.54% w/w5,5′-dimethyl-2,2′- Not determined 99 dipyridyl lotion Formula 27-08-020.74% w/w 5,5′-dimethyl-2,2′- Not determined 100 dipyridyl lotionFormula 26-08-10 0% (Vehicle) 5,5′-dimethyl-2,2′- Not determined 15dipyridyl lotion Formula 26-08-04

The results demonstrate that 5,5′-dimethyl-2,2′-dipyridyl formulation isa good ovicide when it is in a lotion (Formula 07-08-04) (Formula11-08-14 and Formula 11-08-13) composition at a concentration of 0.37%w/w. However, the lousicidal activity at this concentration of5,5′-dimethyl-2,2′-dipyridyl is poor in a solvent system that comprisesoctyldodecanol and caprylic/capric triglycerides. Significantly improvedlousicidal activity is seen at the same concentration of5,5′-dimethyl-2,2′-dipyridyl (0.37% w/w) when the solvent systemcomprises benzyl alcohol and mineral oil (e.g., see Formula 11-08-13.This activity is further improved by increasing the concentration of5,5′-dimethyl-2,2′-dipyridyl to 0.54% w/w; (Formula 27-08-02) and 0.74%w/w; (Formula 26-08-10) while maintaining the solvent system comprisingbenzyl alcohol and mineral oil. A similar vehicle lotion composition(i.e., 0.0% 5,5′-dimethyl-2,2′-dipyridyl composition—Formula 26-08-04)did not demonstrate any significant lousicidal activity, indicating thatthe solvent system per se is not contributing significantly to theefficacy of the pediculicidal compositions. The5,5′-dimethyl-2,2′-dipyridyl lotion compositions exhibit lousicidalactivity when the solvent system comprises benzyl alcohol, as thesolvent, and mineral oil, as the co-solvent. The results also show thatthe 5,5′-dimethyl-2,2′-dipyridyl lotion compositions of Formula 27-08-02and Formula 26-08-10 that contain both mineral oil and benzyl alcohol inthe solvent system exhibit lousicidal activity. The solvent systemappears to activate the lousicidal activity of5,5′-dimethyl-2,2′-dipyridyl in the lotion compositions possibly throughenhancing uptake of the compound by the target parasite and it cantherefore be considered as an activating solvent system.

Example 5. Evaluating Pediculicidal Compositions Against Pediculushumanus humanus

In the development of an effective formulation to kill lice a number offormulations were tested, by varying the composition of the activatingsolvent system and other ingredients of the carrier vehicle. The resultsare provided in Table 6. Increasing the percentage of the surfactantpolysorbate 20 from 1% (32-08-02) to 5% (32-08-10) resulted in adramatic decrease in the lousicidal activity of5,5′-dimethyl-2,2′-dipyridyl. This is in contrast to the teachings ofU.S. Pat. No. 5,858,383, which suggests use of high concentrations ofsurfactants such as polysorbate 20 (10%) or triethanolamine (14.5%) fortopical compositions for ectoparasite treatments in which an airimpermeable composition is used for suffocating lice. Those treatmentsrequired that the compositions of the U.S. Pat. No. 5,858,383 patentmust be applied to the host for more than four hours, preferably 8hours. Moreover, those formulations had little or no effect on the eggsas the formulations were considered to be acting through a suffocationmethod on the crawling stage of the lice lifecycle. In contrast, thecompositions of the current invention have a rapid (about 10 minutes)pharmacological effect due to the actions of the metal chelating agent,5,5′-dimethyl-2,2′-dipyridyl. Moreover, the compositions of the presentinvention are effective against both the lice and the eggs. Furthermore,the composition and the concentration of the surfactant in the inventiondescribed here is shown to be important in the formulation insofar as itenhances the efficacy of the active compound,5,5′-dimethyl-2,2′-dipyridyl against the lice and eggs, rather than thesurfactant alone having a lice killing effect per se. This is supportedby poor activity of the vehicle formulations.

The results further demonstrate that changing the surfactant from 1%polysorbate 20 to 1% sodium laureth sulphate resulted in a loss oflousicidal activity. It was also discovered that when additionalsolvents were evaluated there was a significant impact on the lousicidalactivity. For example formulations containing no surfactant anddifferent solvent systems, such as 5% Diisopropyl Adipate (02-09-09) or5% Capric/capylic Triglyceride (02-09-10) and 5% Propylene GlycolCaprylate (13-09-14) were less active than the benzyl alcohol/mineraloil solvent system with surfactant (35-08-03), which is consistent withthe results obtained in Example 4

TABLE 6 Assessment of the effects of varying components on lousicidalactivity against Pediculus humanus humanus. Formulation LousicidalEfficacy/ code Components % Mortality 32-08-02   1% Polysorbate 20 96  1% Phenoxyethanol   20% MO 0.74% 5,5′-dimethyl-2,2′-dipyridyl 35-08-10  5% Polysorbate 20 5   1% Phenoxyethanol   20% MO 0.74%5,5′-dimethyl-2,2′-dipyridyl 35-08-03   1% Polysorbate 20 100   2% BA  5% MO 0.55% 5,5′-dimethyl-2,2′-dipyridyl 35-08-11   5% Polysorbate 2010   2% BA   5% MO 0.55% 5,5′-dimethyl-2,2′-dipyridyl 02-09-07   1%sodium laureth sulphate 32   1% Phenoxyethanol   20% MO 0.74%5,5′-dimethyl-2,2′-dipyridyl 02-09-09   5% Diisopropyl Adipate 13   1%Phenoxyethanol   20% MO 0.74% 5,5′-dimethyl-2,2′-dipyridyl 02-09-10   5%Capric/capylic Triglyceride 31   1% Phenoxyethanol   20% MO 0.74%5,5′-dimethyl-2,2′-dipyridyl 13-09-14   5% Propylene Glycol Caprylate 10  2% BA   5% MO 0.55% 5,5′-dimethyl-2,2′-dipyridyl “BA” = benzyl alcohol“MO” = mineral oil

These results clearly demonstrate the major effect that changingsurfactant percentage and composition had on lousicidal activity. Thisdata supported the decision for a low surfactant concentration (1%) ofpolysorbate 20 in the preferred formulation. In addition, the above dataalso support the advantages of the benzyl alcohol/mineral oilcombination as an activating solvent system to enhance the activity of5,5′-dimethyl-2,2′-dipyridyl.

Example 6. Evaluation of Lousicidal Efficacy of Compositions AgainstPediculus humanus humanus

TABLE 7 0.74% w/w and 0% (Vehicle) 5,5′-dimethyl-2,2′-dipyridylcompositions and lice efficacy data. 0.74% w/w 5,5′- 0% (Vehicle)dimethyl-2,2′- 5,5′-dimethyl- dipyridyl 2,2′-dipyridyl 17-09-27 17-09-13Quantity Quantity Component (% w/w) (% w/w) Function5,5′-dimethyl-2,2′-dipyridyl 0.74 — Metal chelating agent Benzyl Alcohol2.00 2.00 Solvent/Preservative Mineral Oil 24.00 24.00 Co-solventCarbomer 0.20 0.20 Thickening agent Trolamine 0.25 0.25 pHAdjuster/surfactant Polysorbate 20 1.00 1.00 surfactant Purified Water71.81 72.55 Carrier/Aqueous solvent Total 100.00 100.00 LousicidalEfficacy/% Mortality 100% 30%

Table 7 shows the results of a study comparing the mortality rate of aformulation containing the metal chelating agent and an activatingsolvent system to a formulation where the metal chelating agent isabsent. The 0.74% formulation of 5,5′-dimethyl-2,2′-dipyridyl results ina 100% mortality rate, indicating that the composition has excellentlousicidal activity. This is in contrast to the vehicle treated group,where there was low (30%) lousicidal efficacy. This data is consistentwith the previous examples which indicate that the composition andconcentration of the carrier vehicle ingredients, notably the activatingsolvent system and surfactant compositions and concentrations, areimportant to optimise the efficacy of the active ingredient,5,5′-dimethyl-2,2′-dipyridyl.

This formulation including 0.5% BHT was also evaluated for its ovicidalactivity. See Table 8.

TABLE 8 Evaluation of in vitro ovicidal efficacy of compositions againstPediculus humanus humanus comparing 0.74% w/w5,5′-dimethyl-2,2′-dipyridyl and 0% (Vehicle). 0.74% w/w 0% (Vehicle)5,5′-dimethyl- 5,5′-dimethyl- 2,2′-dipyridyl 2,2′-dipyridyl 17-09-3717-09-35 Component Quantity Quantity 5,5′-dimethyl-2,2′-dipyridyl 0.74 —Mineral Oil 24.00 24.00 Carbomer 0.20 0.20 Trolamine 0.2 0.2 BenzylAlcohol 2.00 2.00 Polysorbate 20 1.00 1.00 Butylated Hydroxy Toluene0.50 0.50 Purified Water 71.36 72.1 Total 100.00 100.00 OvicidalEfficacy/ 0 65% % egg hatch

The results shown in Table 8 indicate that 5,5′-dimethyl-2,2′-dipyridylproduces significant ovicidal activity compared to the vehicleformulation which is ineffective in preventing egg hatch. The lousicidaland ovicidal activity of this formulation support that it is a highlyeffective pediculicide, and further reinforce the beneficial effects ofthe activating solvent system in enhancing the activity of5,5′-dimethyl-2,2′-dipyridyl.

Example 7. Evaluation of Ex Vivo Ovicidal Efficacy of5,5′-Dimethyl-2,2′-Dipyridyl (Abametapir) Against Pediculus humanusCapitis

The following formulation was used in the ex vivo study (Table 9)

TABLE 9 0.74% w/w 0% (Vehicle) 5,5′-dimethyl- 5,5′-dimethyl-2,2′-dipyridyl 2,2′-dipyridyl Component Quantity Quantity5,5′-dimethyl-2,2′-dipyridyl 0.74 — Mineral Oil 24.00 24.00 Carbomer0.15 0.15 Trolamine 0.2 0.2 Benzyl Alcohol 2.00 2.00 Polysorbate 20 1.001.00 Butylated Hydroxy Toluene 0.50 0.50 Purified Water 71.41 72.15Total 100.00 100.00

In this study the formulation as listed in Table 9 containing 0.74%5,5′-dimethyl-2,2′-dipyridyl, (abametapir), was evaluated in adouble-blind, vehicle-controlled randomized clinical trial. The primaryaim of the trial was to evaluate the ovicidal efficacy of a singleapplication of abametapir lotion 0.74% w/w intended for the treatment ofhead lice. The primary end point was the proportion of hatched eggspre-treatment relative to proportion of hatched eggs post-treatment forthe formulation containing abametapir and vehicle treated eggs followinga 14 day incubation.

This ex vivo study involved identifying subjects with an active headlice infestation (active being defined as the presence of at least 3live lice and at least 10 undamaged eggs). A minimum of 5 undamaged eggswere collected both pre and post treatment and their predicted viabilityassessed under a dissecting microscope before being incubated in atemperature and humidity controlled incubator (30° C. and 60% RH) for 14days to provide adequate time for the eggs to hatch. After 14 days eggswere assessed as either hatched, unhatched, or partially hatched.Results are presented in Table 10.

TABLE 10 0.74% Abametapir lotion Vehicle Lotion N = 25 N = 25 Egg hatchPre-treatment 93.3% (111/119 eggs) 79.5% (93/117 eggs) Egg hatchPost-treatment   0% (130/130 eggs)*   36% (49/136 eggs) Total absolutereduction 92.9% 42.3% in hatch rate (CI 95%) The treatment difference50.6% p < 0.0001 *Data demonstrates 100% ovicidal efficacy

Table 10 contains data demonstrating a highly significant reduction inthe number of eggs that hatched in the 0.74% abametapir treated eggscompared to the vehicle lotion. Abametapir reduced the hatch rate from93.3% to 0% as compared to vehicle which reduced the hatch rate from79.5% to 36.0%. This data clearly demonstrates that 100% of all eggstreated with abametapir failed to hatch. Using a generalized estimatingequation model to account for the correlation of eggs within subject,the absolute reduction in hatch rate for the abametapir arm was 92.9%(with a 95% confidence interval of 86.5 to 99.4) compared to an absolutereduction of 42.3% (95% confidence interval of 30.2 to 54.4) for thevehicle arm. The treatment difference in the absolute reduction of hatchrates (abametapir minus Vehicle) was 50.6% (p-value<0.0001, with a 95%confidence interval of 36.9 to 64.3).

Example 8. In Vivo Efficacy of 5,5′-Dimethyl-2,2′-Dipyridyl in Treatinga Head Lice Pediculus humanus capitis Infestation

One hundred and forty two (142) pediatric and adult subjects, three (3)years of age or older, with an active head lice infestation wereenrolled in the study. This study assessed the efficacy of a singleapplication of 2 different dose levels (0.37% w/w and 0.74% w/w of5,5′-dimethyl-2,2′-dipyridyl) compared to a vehicle control. Theformulations were prepared as described in Table 9. Subjects weretreated for 10 minutes with a lotion containing one of two dose levelsof 5,5′-dimethyl-2,2′-dipyridyl or the vehicle lotion. After 10 minutesthe lotion was rinsed out of the subjects hair with water and toweldried. At day 1, 7 and 14 post treatment the hair was examined for thepresence of live lice. If any live lice were detected on any of thethree visits the subject was deemed a treatment failure. The primaryendpoint to the study was that proportion of subjects who were lice freeat day 14. Results from this study indicated that both concentrations of5,5′-dimethyl-2,2′-dipyridyl demonstrated statistically significant andclinically relevant treatment success compared to the vehicle controlgroup. The primary efficacy results showed that 67.4% of subjects in the0.37% treatment group and 85.7% of subjects in the 0.74% treatment grouphad treatment success compared to 23.4% of subjects in the vehicle group(p<0.001). The safety results demonstrated that a single application of5,5′-dimethyl-2,2′-dipyridyl at two dose levels 0.37% w/w and 0.74% w/wwas safe and well tolerated.

Example 9. In Vivo Efficacy of 5,5′-Dimethyl-2,2′-Dipyridyl in Treatinga Head Lice Pediculus humanus capitis Infestation

A total of seven hundred and four (704) pediatric and adult subjects,six (6) months of age or older, with an active head lice infestationwere enrolled in two separate Phase 3 studies. These studies assessedthe efficacy of a single application of 0.74% w/w abametapir compared toa vehicle control (refer Table 9, above). Subjects were treated for 10minutes with a lotion containing abametapir or the vehicle lotion alone.After 10 minutes the lotion was rinsed out of the subjects hair withwater and towel dried. At day 1, 7 and 14 post treatment the hair wasexamined for the presence of live lice. If any live lice were detectedon any of the three visits the subject was deemed a treatment failure.The primary endpoint to the study was that proportion of index subjects(youngest member of the household with at least 3 live lice at thecommencement of the study) who were lice free at all follow-up visitsthrough day 14. Results from these studies indicated that 0.74%abametapir lotion demonstrated statistically significant and clinicallyrelevant treatment success compared to the vehicle control group. Theprimary efficacy results showed that 81.1% (study 1) and 81.8% (study 2)of subjects in the 0.74% treatment group had treatment success comparedto 50.9% (study 1) and 47.2% (study 2) of subjects in the vehicle group(p=0.001) study land (p<0.001) study 2. The safety results demonstratedthat a single application of abametapir 0.74% w/w was safe and welltolerated.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specified embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

Any discussion of documents, acts, materials, devices, articles or thelike which was included in the present specification is solely for thepurpose of providing a context for the present invention. It is not tobe taken as an admission that any or all of these matters form part ofthe prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed in any country beforethe priority date of each claim of this application.

What is claimed is:
 1. A composition comprising:5,5′-dimethyl-2,2′-dipyridyl is present in an amount from 0.5% to 1% byweight; benzyl alcohol is present in an amount from 1% to 3% by weight;mineral oil is present in an amount from 20% to 30% by weight; water ispresent in an amount from 60% to 90% by weight; carbomer is present inan amount from 0.1% to 0.5% by weight; trolamine is present in an amountfrom 0.1% to 1% by weight; butylated hydroxy toluene is present in anamount from 0.2% to 1% by weight; and polysorbate 20 is present in anamount from 0.5 to 1% by weight.
 2. The composition of claim 1, whereinsaid composition is a lotion, cream or gel composition comprising 0.74%by weight 5,5′-dimethyl-2,2′-dipyridyl.
 3. The composition of claim 1,wherein said composition is a lotion or gel composition comprising 24%by weight mineral oil.
 4. The composition of claim 1, wherein saidcomposition is a lotion or gel composition comprising 2% by weightbenzyl alcohol.
 5. The composition of claim 1, comprising 2% by weightbenzyl alcohol, 24% mineral oil, 1% polysorbate 20 and 0.74%,5,5′-dimethyl-2,2′-dipyridyl and said composition exhibits a greaterlousicidal activity than a composition that comprises benzyl alcohol,mineral oil, and polysorbate 20 in the same weight percent, but thatdoes not comprise 5,5′-dimethyl-2,2′-dipyridyl.
 6. The composition ofclaim 1, comprising 2% by weight benzyl alcohol, 24% mineral oil, 1%polysorbate 20 and 0.74%, 5,5′-dimethyl-2,2′-dipyridyl and saidcomposition exhibits a greater ovicidal and lousicidal activity than acomposition that comprises benzyl alcohol, mineral oil, and polysorbate20 in the same weight percent, but that does not comprise5,5′-dimethyl-2,2′-dipyridyl.
 7. An aqueous composition for topicalapplication to a subject comprising by weight: 0.74%5,5′-dimethyl-2,2′-dipyridyl; 24% mineral oil; 0.15% Carbomer; 0.20%Trolamine; 2.00% benzyl alcohol, 1% polysorbate 20, 0.5% butylatedhydroxytoluene and balance purified water.
 8. A method of treating alice infestation, the method comprising topically applying to a hosthaving a lice infestation an effective amount of a composition accordingto claim
 1. 9. The method of claim 8, wherein topical application ofsaid composition kills lice and inhibits egg hatching.
 10. The method ofclaim 8, wherein topical application of said composition to said hostkills more lice than a vehicle composition comprising the samecomponents except for 5,5′-dimethyl 2,2′-dipyridyl.